BSc, PhD Paul J. Simmons (Chief Hospital Scientist), BSc, PhD Jean-Pierre Levesque (RL Clifford Fellow), BSc, PhD Andrew C.W. Zannettino (Research Officer)
{"title":"4 Adhesion molecules in haemopoiesis","authors":"BSc, PhD Paul J. Simmons (Chief Hospital Scientist), BSc, PhD Jean-Pierre Levesque (RL Clifford Fellow), BSc, PhD Andrew C.W. Zannettino (Research Officer)","doi":"10.1016/S0950-3536(97)80022-4","DOIUrl":"10.1016/S0950-3536(97)80022-4","url":null,"abstract":"<div><p>In the adult mammal, haemopoiesis is restricted to the extravascular compartment of the bone marrow (BM) where primitive haemopoietic stem cells (HSC) and their clonogenic progeny develop in intimate contiguity with a heterogeneous population of stromal cells that comprise the haemopoietic micro-environment (HM). Although the importance of cellular interactions between primitive haemopoietic progenitor cells (HPC) and marrow stromal cells is well established, precise definition of the nature of many of these interactions at the molecular level is lacking and remains an objective of fundamental importance to understanding of haemopoietic regulation. Current data suggest that a wide variety of cell surface molecules representing several adhesion molecule superfamilies, including integrins, selectins, sialomucins and the immunoglobulin gene superfamily, are involved in supporting cell-cell and cell-extracellular matrix (ECM) interactions. These diverse CAM-ligand interactions, rather than simply serving to initiate and maintain contact between HPC and stromal cells and ECM components, also have an additional, more direct role in controlling the growth and development of primitive haemopoietic cells.</p></div>","PeriodicalId":77029,"journal":{"name":"Bailliere's clinical haematology","volume":"10 3","pages":"Pages 485-505"},"PeriodicalIF":0.0,"publicationDate":"1997-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S0950-3536(97)80022-4","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20349218","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"9 Granulocyte colony-stimulating factor receptor mutations in severe chronic neutropenia and acute myeloid leukaemia: biological and clinical significance","authors":"PhD Ivo P. Touw (Staff Scientist)","doi":"10.1016/S0950-3536(97)80027-3","DOIUrl":"10.1016/S0950-3536(97)80027-3","url":null,"abstract":"<div><p>Blood cell formation is governed by the haemopoietic growth factors that control the proliferation, maturation and survival of the haemopoietic progenitor cells via activation of receptors expressed on the cell membrane. Most of these receptors share structural features and have been grouped in the haemopoietin or class I receptor superfamily. Recently considerable progress has been made in elucidating the regions critical for the function of these receptors and the signal transduction mechanisms that they activate. Moreover, it has become clear that certain clinical haematological conditions can be linked to specific defects in these receptors. The significance of defects in the receptor for granulocyte colony-stimulating factor (G-CSF) in the pathogenesis of severe congenital neutropenia and acute myeloid leukaemias is discussed.</p></div>","PeriodicalId":77029,"journal":{"name":"Bailliere's clinical haematology","volume":"10 3","pages":"Pages 577-587"},"PeriodicalIF":0.0,"publicationDate":"1997-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S0950-3536(97)80027-3","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20349223","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
MBBS, FRACP Paul G. Ekert (PhD Student), MBBS, BMedSci, PhD David L. Vaux (Investigator)
{"title":"8 Apoptosis, haemopoiesis and leukaemogenesis","authors":"MBBS, FRACP Paul G. Ekert (PhD Student), MBBS, BMedSci, PhD David L. Vaux (Investigator)","doi":"10.1016/S0950-3536(97)80026-1","DOIUrl":"10.1016/S0950-3536(97)80026-1","url":null,"abstract":"<div><p>Apoptosis, or physiological cell death, is the way in which unwanted cells are removed. The majority of cells formed during haemopoiesis are destined to die by apoptosis before they are fully differentiated, and homeostasis of cell number is maintained by a balance between mitosis and apoptosis. Many haematological malignancies are associated with changes in the number of cells undergoing apoptosis, which may be a direct or an indirect effect. Genetic mutations that prevent cell death cause cells to accumulate and can eventually lead to malignancy. Alternatively, oncogenic mutations that lead to increased cell production can indirectly cause a decrease in apoptosis in some populations and an increase in others. Chemotherapeutic drugs may kill cells directly, or indirectly by inducing apoptosis as a stress response. Therapeutic strategies are evolving to increase the propensity of malignant cells to die by either means and to mitigate side effects by reducing apoptosis in non-malignant cells.</p></div>","PeriodicalId":77029,"journal":{"name":"Bailliere's clinical haematology","volume":"10 3","pages":"Pages 561-576"},"PeriodicalIF":0.0,"publicationDate":"1997-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S0950-3536(97)80026-1","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20349222","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
BSc, PhD Gerard J. Graham (Staff Scientist and Group Head)
{"title":"7 Growth inhibitors in haemopoiesis and leukaemogenesis","authors":"BSc, PhD Gerard J. Graham (Staff Scientist and Group Head)","doi":"10.1016/S0950-3536(97)80025-X","DOIUrl":"10.1016/S0950-3536(97)80025-X","url":null,"abstract":"<div><p>The haemopoietic stem cell occupies a central position in the hierarchy of the haemopoietic system and it is at this cellular level that all haemopoietic function can be ultimately regulated. Much effort has thus gone into characterizing regulators of stem cell proliferation with a view to enhancing our understanding of the regulation of this important cell, and in addition to examining the potential clinical roles of such stem cell active factors. We focus on inhibitors of haemopoietic stem cell proliferation and review their molecular and cellular biology and potential clinical usefulness in cancer therapy. The potential roles of inhibitory molecules in the pathogenesis of leukaemias are also discussed.</p></div>","PeriodicalId":77029,"journal":{"name":"Bailliere's clinical haematology","volume":"10 3","pages":"Pages 539-559"},"PeriodicalIF":0.0,"publicationDate":"1997-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S0950-3536(97)80025-X","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20349221","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
PhD Rob E. Ploemacher (Senior Lecturer/Associate Professor)
{"title":"1 Stem cells: characterization and measurement","authors":"PhD Rob E. Ploemacher (Senior Lecturer/Associate Professor)","doi":"10.1016/S0950-3536(97)80019-4","DOIUrl":"10.1016/S0950-3536(97)80019-4","url":null,"abstract":"<div><p>The process of blood formation is sustained throughout an individual's life by a small population of haemopoietic stem cells (HSCs). The HSC compartment represents a hierarchy of HSC subsets with decreasing proliferative ability. This heterogeneity is reflected in the varying time periods that HSCs may contribute to the initiation and maintenance of donor-type haemopoietic multilineage chimerism in vivo. The phenotype of HSC is incompletely defined rendering morphological or flow cytometric quantitation unreliable. Functional HSC assays, both in vitro (CAFC, LTC-IC) and in vivo (repopulation of NOD/SCID mice) may be superior to phenotypic analysis; however, such assays have not been truly validated in a human transplant setting.</p><p>The quiescence and proliferation of HSCs is highly regulated by the stroma in haemopoietic organs. Many of the cytokines that have been cloned in recent years are actually elaborated and presented by the haemopoietic organ stroma and are supposed to serve as local regulators in order to gain specificity and avoid pleitropic and thus undesired side effects. Most probably, additional stroma-derived factors will be characterized as suggested by the observation that HSCs produce more progeny in stroma-contact than in its absence or in stroma-conditioned medium, irrespectively of the exogenous cytokines included.</p><p>Stem cells are considered to possess the ability to self-renew and are therefore attractive vehicles for gene therapy. The same assumed characteristic fuels attempts to amplify their numbers ex vivo, and is expected to enable more rapid haemopoietic recovery of conditioned recipients as well as enlarge HSC grafts of insufficient size before actual transplantation.</p></div>","PeriodicalId":77029,"journal":{"name":"Bailliere's clinical haematology","volume":"10 3","pages":"Pages 429-444"},"PeriodicalIF":0.0,"publicationDate":"1997-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S0950-3536(97)80019-4","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20350590","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
PhD John Groffen (Professor of Pathology) , PhD Nora Heisterkamp (Professor of Pathology)
{"title":"1 The chimeric BCR-ABL gene","authors":"PhD John Groffen (Professor of Pathology) , PhD Nora Heisterkamp (Professor of Pathology)","doi":"10.1016/S0950-3536(97)80002-9","DOIUrl":"10.1016/S0950-3536(97)80002-9","url":null,"abstract":"<div><p>The 1982 discovery that in chronic myeloid leukaemia (CML) the <em>ABL</em> proto-oncogene is translocated to the <em>BCR</em> gene located on chromosome 22 initiated many studies on the structural organization and function of these genes. The nucleotide sequence of the entire <em>BCR</em> and major parts of the <em>ABL</em> gene has now been determined. However, the actual cause of the fusion of <em>BCR</em> with <em>ABL</em> remains essentially unknown. Mouse models have been helpful to unravel the normal cellular function of BCR and ABL, as well the activity of BCR-ABL, although a single mechanism explaining the transforming activity of the latter has not been discovered. The cause of progression of the disease remains unknown, and no single genetic abnormality has been linked to the blast phase of CML. Much has been learned concerning the molecular biology of CML, but answers to the fundamental questions above may be expected in the coming years in parallel to increasing knowledge of genome structure, signal transduction and cell cycle control.</p></div>","PeriodicalId":77029,"journal":{"name":"Bailliere's clinical haematology","volume":"10 2","pages":"Pages 187-201"},"PeriodicalIF":0.0,"publicationDate":"1997-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S0950-3536(97)80002-9","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20305403","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
MD Moshe Talpaz (Professor of Medicine, Chairman) , MD Hagop M. Kantarjian (Chief) , MD Susan O'Brien , MD Razelle Kurzrock
{"title":"7 The M.D. Anderson Cancer Center experience with interferon-α therapy in chronic myelogenous leukaemia","authors":"MD Moshe Talpaz (Professor of Medicine, Chairman) , MD Hagop M. Kantarjian (Chief) , MD Susan O'Brien , MD Razelle Kurzrock","doi":"10.1016/S0950-3536(97)80008-X","DOIUrl":"10.1016/S0950-3536(97)80008-X","url":null,"abstract":"","PeriodicalId":77029,"journal":{"name":"Bailliere's clinical haematology","volume":"10 2","pages":"Pages 291-305"},"PeriodicalIF":0.0,"publicationDate":"1997-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S0950-3536(97)80008-X","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20307174","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
MD, PhD, MRCPath Junia V. Melo (Senior Lecturer in Haematology)
{"title":"2 BCR-ABL gene variants","authors":"MD, PhD, MRCPath Junia V. Melo (Senior Lecturer in Haematology)","doi":"10.1016/S0950-3536(97)80003-0","DOIUrl":"10.1016/S0950-3536(97)80003-0","url":null,"abstract":"<div><p>The <em>BCR-ABL</em> hybrid gene, the main product of the t(9;22)(q34;q11) translocation, is found in the leukaemic clone of at least 95% of CML patients. The fusion protein encoded by <em>BCR-ABL</em> varies in size, depending on the breakpoint in the <em>BCR</em> gene. Three breakpoint cluster regions have been characterized to date: major (M-<em>bcr</em>), minor (m-<em>bcr</em>) and micro (μ-<em>bcr</em>). The overwhelming majority of CML patients have a p210 <em>BCR-ABL</em> gene (M-<em>bcr</em>), whose mRNA transcripts have a b3a2 and/or a b2a2 junction. There is apparently no significant difference between patients with a 5′ or a 3′ M-<em>bcr</em> breakpoint, except maybe for a slight predominance of b3a2-expressing cases among those with increased platelet counts (ET-like syndrome). The smallest of the fusion proteins, p190<sup><em>BCR-ABL</em></sup>, (m-<em>bcr</em> breakpoint) is principally associated with Ph-positive ALL. Rare cases of CML are due to a p190-type of <em>BCR-ABL</em> gene and, in these, the disease tends to have a prominent monocytic component, resembling CMML. CML resulting from a p230 <em>BCR-ABL</em> gene (μ-<em>bcr</em> breakpoint) is also rare, and has been associated with the CNL variant and/or with marked thrombocytosis. Exceptional CML cases have been described with <em>BCR</em> breakpoints outside the three defined cluster regions, or with unusual breakpoints in <em>ABL</em> resulting in <em>BCR-ABL</em> transcripts with b2a3 or b3a3 junctions, or with aberrant fusion transcripts containing variable lengths of intronic sequence inserts. The reciprocal <em>ABL-BCR</em> gene found in the derivative 9q+ chromosome of the t(9;22) is transcriptionally active in nearly two-thirds of CML patients but has not been shown so far to have a functional role in CML. ‘Ph-negative CML’ comprises cases of typical CML in whom the <em>BCR-ABL</em> gene can be detected by molecular methods and others who are genuinely <em>BCR-ABL</em> negative and usually have an atypical disease phenotype.</p></div>","PeriodicalId":77029,"journal":{"name":"Bailliere's clinical haematology","volume":"10 2","pages":"Pages 203-222"},"PeriodicalIF":0.0,"publicationDate":"1997-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S0950-3536(97)80003-0","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20305404","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"13 Assessing residual leukaemia","authors":"PhD Nicholas C.P. Cross (Senior Lecturer)","doi":"10.1016/S0950-3536(97)80014-5","DOIUrl":"10.1016/S0950-3536(97)80014-5","url":null,"abstract":"<div><p>For the great majority of patients with chronic myeloid leukaemia (CML), the Philadelphia (Ph) chromosome is a specific marker of the malignant clone. The standard method to assess the quality of remission in these patients is cytogenetic analysis of bone marrow derived metaphases. However, the molecular definition of the t(9;22) and its consequences has enabled other tests to be developed that can specifically detect CML cells. Fluorescence in situ hybridization (FISH) analyses chromosomes to detect either the juxtaposition of <em>BCR</em> and <em>ABL</em> sequences or the disruption of these genes; Southern blotting analyses genomic DNA to determine whether the <em>BCR</em> gene is rearranged; reverse-transcriptase polymerase chain reaction (RT-PCR) analyses RNA to determine the presence or absence of <em>BCR-ABL</em> transcripts; Western blotting analyses cell lysates to determine the presence or absence of <em>BCR-ABL</em> protein. Each of these techniques has particular advantages and pitfalls but in general they may be used to replace or at least to reduce the frequency of conventional cytogenetic analysis. Partly because of economic factors and the lack of standardization or effective quality control, these assays are still largely restricted to research laboratories. The sensitivity with which residual leukaemia can be detected suggests that FISH, Southern blotting and Western blotting are likely to be most useful in assessing patient response to interferon-α or other forms of treatment that typically induce partial remission. RT-PCR is by far the most sensitive assay and is probably most appropriate for monitoring patients who are in complete remission.</p></div>","PeriodicalId":77029,"journal":{"name":"Bailliere's clinical haematology","volume":"10 2","pages":"Pages 389-403"},"PeriodicalIF":0.0,"publicationDate":"1997-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S0950-3536(97)80014-5","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20307130","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
MD Susan O'Brien, PhD Peter F. Thall, PhD Michael J. Siciliano
{"title":"5 Cytogenetics of chronic myelogenous leukaemia","authors":"MD Susan O'Brien, PhD Peter F. Thall, PhD Michael J. Siciliano","doi":"10.1016/S0950-3536(97)80006-6","DOIUrl":"10.1016/S0950-3536(97)80006-6","url":null,"abstract":"<div><p>The Philadelphia (Ph) chromosome is present in the leukaemic cells of most patients with chronic myelogenous leukaemia. Variant translocations occur in 10% of patients but breakpoints on chromosomes 9 and 22 remain the same, so prognosis of these patients is unchanged. Clonal evolution is infrequent in chronic phase and its significance depends on the specific chromosome involved, the number of metaphases affected and the timing in the chronic phase. The majority of patients in blastic phase demonstrate clonal evolution; three specific abnormalities (+Ph, +8 and isochromosome 17q) are present in 70% of patients. Loss of the Ph chromosome on therapy is associated with prolonged survival. For monitoring these events conventional G-band cytogenetics (CG) is essential at presentation to characterize the disease cytogenetically, while fluorescence in situ hybridization (FISH) on hypermetaphase preparations (hypermetaphase FISH (HMF)) is important for establishing the specific frequency of Ph<sup>+</sup> cells. During treatment FISH on interphase cells (I-FISH) can monitor the level of Ph<sup>+</sup> cells in circulation, while CG may be used to identify any suspected clonal evolution. Where I-FISH is negative, HMF is essential to evaluate minimal residual disease.</p></div>","PeriodicalId":77029,"journal":{"name":"Bailliere's clinical haematology","volume":"10 2","pages":"Pages 259-276"},"PeriodicalIF":0.0,"publicationDate":"1997-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1016/S0950-3536(97)80006-6","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20307172","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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